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Cognitive Deficits in Neurodevelopmental Disorders (Schizophrenia) Carrie E. Bearden, Ph.D. Psychiatry and Biobehavioral Sciences and Psychology Semel Institute for Neuroscience and Human Behavior University of California, Los Angeles [email protected] Today’s Lecture • Phenomenology • Genetics • What is inherited? -cognitive/structural brain changes - cellular signaling changes • Genetics Part II- high risk models Schizophrenia literally means “split-mind” • “Schizm” or splintering of the “phren” or mind • Not multiple personality disorder! • “I call dementia precox schizophrenia because, as I hope to show, the splitting of the different psychic functions is one of its most important features. In each case there is a more or less clear splitting of the psychological functions: as the disease becomes distinct, the personality loses its unity”. – -Eugen Bleuler (1857-1939) • Splintering of various mental faculties (thought, affect, etc.) so that they are no longer coordinated • Onset between the late teens and early 30s • Onset for women usually later (25 - mid-30s) Components • Thought Form (loosening of associations, incoherence, neologisms) • Thought Content (delusions of persecution, grandeur, thought control) • Attention and Perception (“over-attention”, hallucinations, voices) • Affect, Motivation, Social Functioning (blunted or silly affect; anhedonia; social withdrawal) • Cognitive deficits DSM-V Criteria • Either hears voices or has bizarre delusions, or has two or more of following, for 1-month or more – – – – – Delusions Hallucinations Formal thought disorder Grossly disorganized behavior or catatonia Flat or inappropriate affect • Deterioration from a previous level of functioning in work, social relations, and/or self-care • Continuous signs of the disturbance for at least 6 months, including prodromal/residual symptoms Delusions • False beliefs involving misinterpretation of surroundings • Persecutory (most common): person believes he/she is being tormented, ridiculed, spied on i.e. someone or thing out to get him/her • Referential (very common): certain environmental cues are directed at him/her (e.g. from newspaper, gesture, TV, song lyrics, etc.) Delusions (continued) • Bizarre delusions: clearly implausible, doesn’t derive from ordinary life experiences – – – – Thought insertion Thought withdrawal Thought broadcasting Delusion of control • Person must have conviction about delusion, despite clear contradictory evidence • Must not be consistent with cultural norms Hallucinations • False Perceptions • Hearing things that other people don’t hear • Seeing things that others don’t see • Smelling, tasting, or feeling unusual sensations that other people don’t experience • Conviction & in the absence of other stimuli • Not while falling asleep or waking up Other Symptoms • Disorganized Thinking: – Ascertained through speech – Loose associations, “word salad,” tangential speech – Must impair communication • Disorganized Behavior – Problems in goal-directed behavior – Can range from child-like silliness to unpredictable agitation (shouting and swearing) – Appearance: can appear disheveled, unusual clothing – Inappropriate sexual behavior e.g. public masturbation • Catatonic Motor Behavior – marked decrease in reactivity to environment – maintaining rigid posture and resisting effort to be moved Negative Symptoms • Negative Symptoms: diminution or loss of normal functioning – Affective flattening: restriction in range and intensity of emotional expression (affect) – Alogia (poverty of speech): decrease in production of thoughts/speech – Avolition: decrease in goal-directed behavior Heterogeneity of Schizophrenia • Symptoms - not all are present in every case, can differ across time in a case • Age at onset - differs markedly between males (late teens) and females (mid twenties) • Premorbid functioning - for some, comes from ‘out of blue’, for others, insidious • Course of illness - episodic versus chronic • Differential diagnosis -Psychotic symptoms may also be present in mania and depression, or in substance abuse and organic brain syndromes (dementia) Gerald 0-3:15 Part I: http://www.youtube.com/watch?v=gGnl8dqEoPQ Part II: http://www.youtube.com/watch?v=i6h8Ic-I7R0 What changes in the brain to cause schizophrenia? Schizophrenia as a Genetic Disorder • Evidence for a role of genetics: – Aggregates in families – Closer genetic relationship, risk (e.g. MZ twin risk = ~50%, while DZ = ~13-15%) More complicated than just genetics… • not Mendelian: – Not fully penetrant (MZ twin risk is not 100%) – Some symptoms can arise from non-genetic causes (I.e. psychosis from drug abuse = phenocopy) – Affected/unaffected boundary not clear- spectrum disorder – Multiple genes: a combination of genes risk • Environmental factors : – prenatal influences - birth complications, maternal influenza, maternal stress – environmental factors - cannabis use, urban environments Schizophrenia & Genes • Significant genetic component • The mode of transmission is complex, involving many genes and gene-environment interactions • The genes do not produce symptoms, but changes in brain structure and function that make one susceptible to symptoms • Current theory: Schizophrenia is highly polygenic - can result if one has a certain critical number of predisposing genes and (at least in some cases) particular environmental stressors (diathesis-stress) Hypothesized Model of Illness Progression Severe Early Insults Disease Genes Viral Infections EnvironmentalToxins Triggers Moderate Disability Biological Vulnerability Cognitiv e Affective Vulnerability Indicators Social Isolation Avolition, School Failure Early Symptoms 108 Genome-Wide Significant Risk Loci! Ripke et al. 2014 ? Schizophrenia Schizophrenia If schizophrenia is genetic, then what are the specific risk factors being inherited? Two possibilities: • Neural changes (brain structure/function) • Cellular signaling changes Neurocognitive impairment as an indicator of genetic liability to schizophrenia Schizophrenia increasingly viewed as extreme end of a set of quantitative traits; neurocognitive deficits possible indicators of this liability. Cognitive impairment is: Present in first-episode schizophrenia and even before illness onset remains relatively stable throughout the course of illness; not accounted for by effects of symptoms or medication; Found among clinically unaffected relatives of SZ patients For cognitive measures, attention found to have moderate to high relative risk in subgroup of families with high genetic loading for schizophrenia (Chen 1998; Egan 2000) Wechsler Intelligence Scale for Children (WISC) Subtest Scores for 7-YearOlds Who Later Developed Schizophrenia, Their Unaffected Siblings, and Nonpsychiatric Comparison Children Niendam et al. AJP 2003 Deficits in Spatial Working Memory Co-Vary with Genetic Liability to Schizophrenia 100 Probands MZ Co-Twins DZ Co-Twins Healthy Controls % Correct 90 80 70 Load 1 Load 3 Memory Set Size Glahn et al., Biological Psychiatry 2003;53:624-626. Load 5 Least Square Mean Number of Words per Trial +/- Standard Error Deficits in Verbal Learning and Recall Co-Vary with Genetic Liability to Schizophrenia 16 Proband MZ-cotwin DZ-cotwin Healthy 14 12 10 8 6 4 2 0 Free Recall van Erp et al. 2007 Cued Recall Trial Type Recognition Hippocampal Volumes across Risk Groups van Erp, T. G. M. et al. Arch Gen Psychiatry 2004;61:346-353. Copyright restrictions may apply. Proportions of medication-naive patients negatively (P=0.0004) associated with hippocampus group contrast effect Slide courtesy of Carol Tamminga -Intelligence, working memory and perceptual organization shared highest genetic variance with schizophrenia (not processing speed) -rg = −0.75 between SZ and IQ; suggests same genes contribute to individual differences in intelligence and to liability to schizophrenia Arch Gen Psychiatry. 2007;64(12):1348-1355. doi:10.1001/archpsyc.64.12.1348 Cognitive Decline as a Predictor of Psychosis in the General Population; Dunedin Birth Cohort IQ was stable across childhood for all groups but declined for the schizophrenia group between ages 13 and 38 (0.39 SD) Meier et al. AJP 2014 Cognition: IQ in Premorbid , Clinical High Risk & Psychosis Phases (in Liu, Keshavan, Tonick, Seidman, SZ Bull 2015)* PRE -0.54 PRO-C -0.81 FE -1.01 CSZ -1.1 FE-CSZ Memory -1.2 to 1.5 *Cross-sectional studies from 4 meta-analyses – L. Seidman PRE: Woodberry, Giuliano & Seidman, 2008; PRO-C: Giuliano et al. 2012; FE: MesholamGately, Giuliano, et al. 2009; CSZ: Heinrichs & Zakzanis, 1998 NAPLS 1 Profile by Group (Seidman et al 2010, Arch Gen Psychiatry) NAPLS2, Submitted – Seidman et al., 2016 Neuropsychological Profile by Diagnostic Group Accounting for Age 0.2 0.0 Z Score -0.2 -0.4 -0.6 -0.8 CHR Non-Converters (n=600) Control CHR Converters (n=89) -1.0 Executive Verbal Abilities Attention/Working Declarative Fx/Visual Abilities Memory Abilities Memory Abilities Task Babble Upsit NAPLS 2 Tests of Retrieval from Semantic Knowledge (subjects with 2+ assessments) WASI Vocabulary Verbal Fluency Smell Identification Trajectories by age centered. Linear mixed effects models adding ‘group’ x ‘time’ as a fixed effect fit the data better than those with only mean age, sex, and maternal education but group by time interaction effects were not significant. NAPLS 2: Tests of Memory (subject with 2+ assessments) Verbal Memory Visual Memory Spatial Working Memory Trajectories centered on age. Linear mixed effects models adding ‘group’ x ‘time’ as a fixed effect fit the data better than those with only mean age, sex, and maternal education but group by time interaction effects were not significant. We are able to observe thinner grey matter in living subjects using MRI Cannon, 2001 Basis of Structural Changes • If people with schizophrenia (for the most part) don’t have full blown symptoms until late adolescence or early adulthood, when or how do these underlying brain changes occur? • Your brain is a dynamic structure, changing substantially across your lifespan. • The genetic and environmental factors that contribute to risk for schizophrenia may do so by directly influencing neural development, or by interacting with ongoing developmental processes. Synaptogenesis and Pruning Neuronal Cell Death/Synaptic Pruning Synaptogenesis Synaptic Density Birth 4yrs-10yrs Adolescence Age • Grey matter changes – Typical Development • synapses are overproduced early in development • across development and during adolescence, normal pruning process occurs eliminating 40% of cortical synapses (Huttenlocher, 1979) Structural Changes Emerge Across Development Overaggresive or accelerated pruning Synaptic Density Psychosis threshold Selemon & Goldman-Rakic Glantz & Lewis Changing Grey Matter Across Adolescence Sun, 2009 Is Neuroanatomic Change Predictive of Psychosis Onset? Cortical thickness change over time among converting CHR subjects (n=35), non-converting CHR (n=239), and healthy controls (n=135) Converters vs. Controls Converters vs. Nonconverters FDR Corrected P-Maps 2 Wald χ =14.82, P=0.0001, AUC=0.71 Cannon et al, Biol Psych 2014 • • • At Sensitivity = 0.60 - Specificity = 0.77 - PPV = 0.40 - NPV = 0.88 • At Sensitivity = 0.78 - Specificity = 0.65 - PPV = 0.37 - NPV = 0.92 Differential GM loss among cases who had not received antipsychotic medications during the inter-scan interval Prefrontal GM loss was significantly correlated with pro-inflammatory index in plasma Summary • Disruption of neural systems part of inherited diathesis to schizophrenia • Both structural and functional brain changes emerge across adolescence • This time period may represent a window in which it is possible to intervene and prevent development of abnormal circuitry If schizophrenia is genetic, then what are the specific risk factors being inherited? Two possibilities: • Neural changes (brain structure/function) • Cellular signaling changes Many of the first psychiatric drugs were discovered serendipitously & led to the production of new hypotheses about the causes of mental disorders The pathophysiology is studied to reveal possible causes Etiology Pathophysiology The mechanisms of action of those treatments are revealed and used to infer pathophysiology Phenomenology Treatment It is noted that certain phenotypes respond to particular interventions The Dopamine Story, Part I • For many years was no effective treatment • Chlorpromazine (Thorazine) – ~ 1950 Synthesized as an anti-histamine to produce sedation – Discovered, by chance, also to have antipsychotic efficacy • Some patients show symptom reduction after prolonged treatment • This is not a general effect of tranquilizers – Categorized as a “neuroleptic” based upon its ability to produce extreme slowness or absence of movement (neurolepsis) The Dopamine Story, Part II • More related drugs were discovered, with common antipsychotic effects and common side effects (Fluphenazine, thioridazine, Haloperidol) • Carlsson and Lindqvist (1963) – Delivered available antipsychotic drugs to rabbits - found that they all elevated the levels of 3-methoxytyramine (3-MT) in brain – 3-MT is the catabolite (breakdown product) of the monoamine dopamine which is produced after COMT breaks it down. Therefore, it seems that these drugs are having an impact on dopaminergic function Affinity for Dopamine Receptors Predicts Antipsychotic Efficacy • All clinically efficacious antipsychotic drugs are DA receptor antagoniststhey block DA receptors. • The specific dopamine receptor they block is the D2 type • D2 receptors most prevalent in striatum Blocking striatal dopamine has antipsychotic effects Creese et al. (1976) Science 192:481-3 The Dopamine Story, Part III • L-dopa treatment of Parkinson’s disease, which helps enhance DA production, can cause psychosis • Long-term or high dose intake of stimulant drugs can elicit psychosis – Increasing problem with treatment of adults for AD/HD • L-dopa augments DA synthesis and release, and stimulant drugs increase DA release. Increasing dopamine can cause psychotic symptoms Summary of evidence: • Certain drugs have been shown to reduce psychotic symptoms • Those drugs were found to be dopamine antagonists • The better the drug was at blocking dopamine, the better an antipsychotic it is. • Drugs that increase dopamine levels can lead to psychosis • What would be the logical conclusion to draw about dopamine from this evidence? BUT…. Initial Dopamine Hypothesis has Limitations • Only about 1/3 of all patients will respond well to one or the other of these pharmacological interventions • All patients treated with these drugs will develop severe side effects that limit compliance • Once again, there is an issue of a therapeutic lag • Even amongst those 1/3 of patients that will respond well to treatment, not all symptoms will be equally affected Drug Effects on Symptoms • Positive symptoms of the disorder are more affected than the other symptoms • Negative and cognitive symptoms are generally not improved with these drug treatments, even when positive symptoms are constrained • “old” D2 antagonist drugs may increase negative and cognitive symptoms (or produce so-called ‘secondary’ negative/cognitive symptoms) Dopamine and the Frontal Lobe • Decrease in dopamine levels in the PFC may be related to cognitive deficits in schizophrenia. • Cognitive deficits and metabolic dysfunction of frontal cortex in schizophrenia reversed by dopamine receptor agonists or drugs that stimulate dopamine release. • Striatal and frontal dopamine levels and effects may differ Dopamine Distribution • Released primarily into: – basal ganglia (striatum) – frontal lobe • Nigrostriatal System – (role in movement) • Mesolimbic System – (role in reinforcement/reward) • Mesocortical System – (role in short-term memory, planning, and problem solving) Dopamine might be PART of the story, but cannot explain everything A New Suspect: Glutamate • NMDA receptor hypofunction hypothesis (Stone et al., 2007,2011) • NMDA receptor antagonists increase glutamate and result in neurotoxic changes in animals Review: Howes et al . Glutamate and dopamine in schizophrenia: An update for the 21st century. J of Psychopharmacology 2015. PCP is an NMDA Antagonist • PCP produces a “non-competitive” blockade of the NMDA receptor. • Ketamine shares this effect. • Schizophrenia may also involve low levels of glutamate PCP (Humans and Animals) PCP and ketamine are NMDA (glutamate receptor) antagonists. They cause a set of symptoms much closer to the full spectrum of schizophrenia symptoms than dopamine agonists do. • Induce positive symptoms – Delusions and hallucinations – Thought disorder • Induce negative symptoms – Social withdrawal – Flattened affect • Induce cognitive symptoms – Working memory, attention, executive function deficits Dopamine and Glutamate • There is an interactive dopamine-glutamate circuitry between the striatum and the cortex. • Low levels of glutamate may be the primary source of other disruptions, including lower prefrontal dopamine (which causes cognitive deficits) and higher striatal dopamine (which causes psychosis). Schizophrenia Genetics, Part II Majority of cases of unknown etiology; But- rare genomic copy number variants (CNVs) may account for a larger proportion of schizophrenia cases than was previously believed. Also provide strong evidence for genetic pleiotropy, challenging widely held views of diagnostic ‘categories’ 22q11.2 microdeletion syndrome (22q11.2DS) is a CNV which conveys the greatest increase in risk for SZ/also highly penetrant for multiple childhood disorders 22q11.2 Microdeletion Syndrome Velocardiofacial/DiGeorge Syndrome Estimated incidence -~ 1/2000 live births (Grati et al 2015) Results from hemizygous deletion of chromosome 22q11 (~3 Mb) Cardiac defects, immune deficiency, craniofacial anomalies Morbid risk of schizophrenia ˜ 25x the general population risk (Bassett et al.2010; Murphy et al.1999); accounts for ~1% of sporadic SZ cases (Stefansson et al., 2008; Karayiorgou et al. 2010) Elevated rates of Autistic Spectrum Disorder (12-50%), ADHD (33-40%) and anxiety disorder (40-50%) in childhood (Schneider et al. 2014; Richards et al. 2014) Jonas et al., Biol Psych 2013 Prevalence of Schizophrenia Spectrum Disorders by Age in 22q11DS (n=1402); 41% of adults age 25+ Total N=1402 Schneider et al AJP 2014 Does Cognitive Decline Predict Psychosis in 22q11DS? (N=430) Vorstman et al JAMA Psychiatry 2015 Verbal IQ decline significantly increased risk for psychosis (OR 3.5; 95% CI=1.77-9.04, p=0.001) Longitudinal Findings: 3-way (brain region x time x group) interactions associated with psychotic symptom change over time Brain Regions associated with Social Processes Green et al Nat Rev Neurosci 2015 Mouse Models of Sz: 22q11.2 Deletion Syndrome Kellendonk et al 2009 Bryan Charnley, Portrait Series http://www.bryancharnley.info/ Apart from my pictures, I regard my illness as completely negative, involving the sufferer in a vicious downward spiral. Current medical practice attempts to suppress both the patient and his symptoms, convenient but evasive. My paintings stand as an attempt to penetrate this wall of silence and I hope they can throw some light on a condition which has largely eluded medical science”. Conventional portrait painted in two sittings. Is it a good likeness? Drug dosage was two 3 mg. tablets of Depixol daily plus two 25 mg. Tryptisol. I was sleeping a lot. 11th to 16th April 1991. Series of slides courtesy of Dr. Robin Murray 20 April ‘Very paranoid’, Bryan writes in the diary. The person upstairs is reading my mind and speaking back to me in a sort of ego crucifixion… The large rabbit ear is because I am confused and extremely sensitive to human voices, like a wild animal’ 6 May ‘I feel like a target for people’s cruel remarks. 18 May ‘My mind seems to be thought-broadcasting very severely and it is beyond my will to do anything about it. I have summed this up by painting my brain as an enormous mouth’ 23 May ‘The blue is there because I feel depressed ….The wavy lines are because just as I feel I am safe, a voice from the street guts me emotionally by its ESP of my conditions… 13 June Bryan has cut out his antidepressant drug completely since 24 May. His selfportrait shows two decapitated egg shells, their contents devoured. ‘The eggs have been emptied like a head stripped of its contents, It has nothing left in it, no more secrets’ Final Portrait Take Home Messages • Schizophrenia is a complex illness with genetic and environmental causes • Disruptions in both glutamatergic and dopaminergic systems implicated in disease pathophysiology • Structural brain changes and concomitant cognitive changes proximal to (prior to?) illness onset • Utility of high-penetrance models: 22q11DS may account for only small proportion of risk for psychotic illness overall, but dysregulated genes/pathways may contribute to broader psychosis susceptibility